11-47341204-C-T

Variant names:

• chr11-47341204-C-T
• rs730880555
• NM_000256.3:c.1831G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PP3_Moderate PP5

The NM_000256.3(MYBPC3):​c.1831G>A​(p.Glu611Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,599,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E611G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:8
• Conservation: PhyloP100: 7.48
• Publications: 6 publications found

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_000256.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 11-47341204-C-T is Pathogenic according to our data. Variant chr11-47341204-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180955.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1831G>A	p.Glu611Lys	missense_variant	Exon 19 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1831G>A	p.Glu611Lys	missense_variant	Exon 19 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1831G>A	p.Glu611Lys	missense_variant	Exon 18 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1831G>A		non_coding_transcript_exon_variant	Exon 19 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000134 AC: 3 AN: 223916 AF XY: 0.0000165

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000995

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1447508 Hom.: 0 Cov.: 36 AF XY: 0.0000111 AC XY: 8 AN XY: 718604

African (AFR) AF: 0.00 AC: 0 AN: 33196

American (AMR) AF: 0.00 AC: 0 AN: 42706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25842

East Asian (EAS) AF: 0.00 AC: 0 AN: 38908

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000145 AC: 16 AN: 1105418

Other (OTH) AF: 0.00 AC: 0 AN: 59874

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74300

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000359 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYBPC3: PS4:Moderate, PM2:Supporting

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hypertrophic cardiomyopathy Uncertain:4

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 611 of the MYBPC3 protein (p.Glu611Lys). This variant is present in population databases (rs730880555, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy, dilated cardiomyopathy, or noncompaction cardiomyopathy (PMID: 21750094, 23054336, 23283745, 24111713, 29447731, 30847666, 31513939, 32369506, 36264615). ClinVar contains an entry for this variant (Variation ID: 180955). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

May 14, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 611 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: PMID: 23054336, 23283745, 24111713, 28971120, 30297972, 30847666, 31513939, 32369506). One of these individuals also carried a different pathogenic variant in the MYBPC3 gene (PMID: 23054336). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 21750094), an individual affected with noncompaction cardiomyopathy (PMID: 29447731), and in an individual affected with an unspecified cardiomyopathy (PMID: 30847666). This variant has been identified in 6/255294 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Oct 31, 2018

Center for Human Genetics, University of Leuven

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypertrophic cardiomyopathy 4 Pathogenic:3

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiomyopathy Pathogenic:1 Uncertain:1

Apr 26, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 611 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 23054336, 23283745, 24111713, 28971120, 30297972, 30847666, 31513939, 32369506, 33495596). One of these individuals also carried a different pathogenic truncation variant in the MYBPC3 gene (PMID: 23054336). It has also been reported in one individual affected with dilated cardiomyopathy (PMID: 21750094), in one individual affected with noncompaction cardiomyopathy (PMID: 29447731), and in one individual affected with an unspecified cardiomyopathy (PMID: 30847666). This variant has been identified in 6/255294 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

May 16, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Pathogenic:1 Uncertain:1

Aug 02, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MYBPC3 c.1831G>A (p.Glu611Lys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is located in the Immunoglobulin I domain (InterPro). Other missense variants around this region have also been reported in HCM patients, such as p.Tyr614Cys, p.Asp610Val, p.Asp610His, p.Asp610Asn, p.Ala609Val, etc., suggesting a notion that the region is important for protein function; however they have conflicting interpretations of pathogenicity ranging from pathogenic to uncertain significance in ClinVar. This variant is absent in 52198 control chromosomes but has been reported in at least nine patients (2 DCM, 7 HCM) from multiple countries. However, there are no co-segregation studies in literature, nor are functional studies. One DCM patient was not comprehensively genotyped (Waldmuller_2014) while another DCM patient also has unspecified mutation(s) (Wang_2014). Thus, it may be possible that it is HCM-specific mutation. This variant was also found in one HCM patient who also carried another frameshift mutation in the same gene; however, phenotypic severity of the patient is not specified. One clinical lab has classified it as pathogenic. Taken together, this variant is classified as Probable Disease Variant (or Likely Pathogenic).

Aug 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E611K variant (also known as c.1831G>A), located in coding exon 19 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1831. The glutamic acid at codon 611 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in multiple hypertrophic cardiomyopathy cohorts, a dilated cardiomyopathy cohort, and a noncompaction cardiomyopathy cohort; however, clinical details were limited and several had additional cardiac variants reported, including at least one patient who was also heterozygous for a pathogenic MYBPC3 alteration (Waldm&uuml;ller S et al. Eur. J. Heart Fail., 2011 Nov;13:1185-92; Miller EM et al. J Genet Couns, 2013 Apr;22:258-67; Zou Y et al. Mol. Biol. Rep., 2013 Jun;40:3969-76; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Ho CY et al. Circulation, 2018 Oct;138:1387-1398; van Waning JI et al. J. Am. Coll. Cardiol., 2018 Feb;71:711-722; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754; Nijenkamp LLAM et al. PLoS One, 2020 May;15:e0232427). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

not specified Uncertain:1

Feb 07, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu611Lys variant in MYBPC3 has been reported in 2 individuals with HCM (Miller 2013, Zou 2013), in 1 individual with DCM (Waldmuller 2011) and in 1 individual with non compaction cardiomyopathy (Waning 2018). Of note, one of these individuals with HCM also carried a pathogenic variant in MYBPC3 (Miller 2013). It is present in CLinVar (ID 180955) (conflicting interpretations). The p.Glu611Lys variant was also identified in 1/27268 of South Asian chromosomes in gnomAD. Computational prediction tools and conservation analysis suggest that the p.Glu611Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu611Lys variant is uncertain.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
CardioboostCm	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Uncertain	2.2	M;.;.
PhyloP100		7.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.8	D;.;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0070	D;.;D
Sift4G	Uncertain	0.029	D;D;D
Vest4		0.98
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.45
gMVP		0.95
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730880555; hg19: chr11-47362755;